Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, which is monitored by the spindle assembly checkpoint (SAC) signaling. As an upstream factor of SAC, the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling. However, the underlying molecular mechanism remains elusive. Here, we demonstrated that the multisite interactions between Mps1 and Ndc80 complex (Ndc80C) govern Mps1 kinetochore targeting. Importantly, we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C. We further identified that Mps1 C-terminal fragment, which contains the protein kinase domain and C-tail, enhances Mps1 kinetochore localization. Mechanistically, Mps1 C-terminal fragment mediates its dimerization. Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1, leading to aberrant mitosis due to compromised SAC function. Taken together, our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.

中文翻译：

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Mps1 二聚化和多位点与 Ndc80 复合物的相互作用使响应性主轴组装检查点信号成为可能。

无错误的有丝分裂取决于染色体与纺锤体微管的准确连接，纺锤体微管由纺锤体组装检查点 (SAC) 信号监测。作为 SAC 的上游因素，Mps1 激酶的精确和动态着丝粒定位对于启动和沉默 SAC 信号传导至关重要。然而，潜在的分子机制仍然难以捉摸。在这里，我们证明了 Mps1 和 Ndc80 复合体（Ndc80C）之间的多位点相互作用控制 Mps1 动粒靶向。重要的是，我们确定了 Mps1 四肽重复结构域和 Ndc80C 之间的直接相互作用。我们进一步确定了包含蛋白激酶结构域和 C 尾的 Mps1 C 端片段，增强了 Mps1 动粒的定位。从机制上讲，Mps1 C 端片段介导其二聚化。C 尾的扰动减弱了 Mps1 的着丝粒靶向和活性，由于 SAC 功能受损导致异常有丝分裂。总之，我们的研究强调了 Mps1 二聚化和与 Ndc80C 的多位点相互作用在启用响应性 SAC 信号传导方面的重要性。